Nitrosothiol esters of diclofenac: Synthesis and pharmacological characterization as gastrointestinal-sparing prodrugs

被引：79

作者：

Bandarage, UK ^{[1
]}

Chen, LQ ^{[1
]}

Fang, XQ ^{[1
]}

Garvey, DS ^{[1
]}

Glavin, A ^{[1
]}

Janero, DR ^{[1
]}

Letts, LG ^{[1
]}

Mercer, GJ ^{[1
]}

Saha, JK ^{[1
]}

Schroeder, JD ^{[1
]}

Shumway, MJ ^{[1
]}

Tam, SW ^{[1
]}

机构：

[1] NitroMed Inc, Bedford, MA 01730 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2000年 / 43卷 / 21期

关键词：

D O I：

10.1021/jm000178w

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Despite its widespread use, diclofenac has gastrointestinal liabilities common to nonsteroidal antiinflammatory drugs (NSAIDs) that might be reduced by concomitant administration of a gastrointestinal cytoprotectant such as nitric oxide (NO). A series of novel diclofenac esters containing a nitrosothiol (-S-NO) moiety as a NO donor functionality has been synthesized and evaluated in vivo for bioavailability, pharmacological activity, and gastric irritation. All S-NO-diclofenac derivatives acted as orally bioavailable prodrugs, producing significant levels of diclofenac in plasma within 15 min after oral administration to mice. At equimolar oral doses, S-NO-diclofenac derivatives (20a-21b) displayed rat antiinflammatory and analgesic activities comparable to those of diclofenac in the carrageenan-induced paw edema test and the mouse phenylbenzoquinone-induced writhing test, respectively. All tested S-NO-diclofenac derivatives (20a-21b) were gastric-sparing in that they elicited markedly fewer stomach lesions as compared to the stomach lesions caused by a high equimolar dose of diclofenac in the rat. Nitrosothiol esters of diclofenac comprise a novel class of NO-donating compounds having therapeutic potential as nonsteroidal antiinflammatory agents with an enhanced gastric safety profile.

引用

页码：4005 / 4016

页数：12

共 43 条

[1] S-nitrosothiols:: a class of nitric oxide-donor drugs [J].